The scientific opportunities identified in the 2011 NICHD Vision Workshop on Reproduction included the need for innovative and safer methods of contraception. Combined hormonal contraceptive methods have been used for more than 50 years and are very effective if used as directed, but failures occur due to incorrect use. Several factors may contribute to irregular use: (1) Concerns about ethinyl estradiol (EE), the synthetic estrogen in most formulations, which is associated with an increased risk of a venous thromboembolism (VTE) as well as nausea and headache. (2) The need for daily attention. Despite the availability of many contraceptive options, the need for innovative contraceptive methods allowing improved compliance is real. In addition, little is known on the effects of contraceptives on the brain, although recent literature showed a neuroprotective, neuroregenerative and promyelinating effect of some, but not all molecules used for contraception in young women. Nestorone (NES), a nonandrogenic progestin currently developed for contraception has also been shovm to have potential beneficial outcomes in inducing and sustaining the regenerative capacity of the brain and also in stimulating the myelin repair in animal models. We propose to develop a novel, user-controlled semi long-acting contraceptive method to address the safety issues surrounding the use of EE as well as the compliance problems related to the need for frequent user attention. This method consists of a vaginal ring delivering 17beta-estradiol (E2), a natural estrogen not associated with increased VTE risk, plus NES, a progestin with potential benefits. The vaginal ring is designed to be used continuously for 3 months. In parallel with an initial clinical study of the NES/E2 vaginal ring, research will be conducted on regenerative capacity of the brain and promyelinating effects of NES + E2 in cell systems and validated animal models at contraceptive doses. This multidisciplinary proposal is consistent with goals identified in the 2011 NICHD Scientific Vision Workshops on Reproduction and Plasticity. Should the results continue to be positive, further research would include clinical evaluation of the NES/E2 ring as a potential safer contraceptive with additional activity (promyelinating effects) for women with multiple sclerosis and/or with a positive effect on the cognitive function.